IAP Antagonists Target cIAP1 to Induce TNFα-Dependent Apoptosis

Vince, James E.; Wong, Wendy Wei-Lynn; Khan, Nufail; Feltham, Rebecca; Chau, Diep; Ahmed, Afsar U.; Benetatos, Christopher A.; Chunduru, Srinivas K.; Condon, Stephen M.; McKinlay, Mark A.; Brink, Robert; Leverkus, Martin; Tergaonkar, Vinay; Schneider, Pascal; Callus, Bernard A.; Köentgen, Frank; Vaux, David L.; Silke, John

doi:10.1016/j.cell.2007.10.037

Cited by 1,016 publications

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“…As previously reported, degradation of c-IAP-1/2 is critical for Tweak/TNFα-or SM/TNFα-induced cell death. 26,28,33 Yet, we observed that the level of Tweak-, agonist LTβR-or CmpAinduced c-IAP1/2 degradation was similar in NIK +/+ and NIK − / − MEFs, indicating that c-IAP1/2 depletion is not compromised in the absence of NIK (Figures 4f and g and Supplementary Figure S4c). Together, these results indicate that NIK acts downstream of complex I formation but upstream or at the level of RIP1/caspase-8 assembly.…”

Section: Resultsmentioning

confidence: 77%

“…Previous studies reported that, at least in certain cell types, Tweak-and SM-induced cell death relied on the NIK-dependent neosynthesis of endogenous TNFα via induction of the classical and/or the alternative NF-κB pathway. 11,26,27,33 We can rule out this possibility in our in vitro and in vivo genetic models. Indeed, we showed that Tweak-, LTβR agonist-or SM-induced NIK stabilization in MEFs is by itself not sufficient to induce cell death and that NIK deficiency protected the MEFs from TNFR1-mediated death induced by exogenous TNFα.…”

Section: Discussionmentioning

confidence: 99%

“…[21][22][23][24][25] Synthetic small molecules mimicking Smac (Smac mimetics (SMs)) emerged as tools to induce c-IAP1/2 depletion and were consequently shown to sensitize particular cancer cell lines to TNFR1-mediated RIP1-dependent death. 11,[26][27][28] Apart from these chemicals, a set of biological ligand of the TNF family, such as lymphotoxin LTα 1 β 2 , CD40L or Tweak, also appeared to target c-IAP1/2 toward the proteasomal and/ or lysosomal degradative pathways. [29][30][31][32][33][34] c-IAP1/2 depletion leads to NIK (NF-κB-inducing kinase) stabilization and the phosphorylation of both IKKα and NF-κB2/p100 prior to the processing of p100 into p52, a pathway defined as the alternative, or non-canonical, NF-κB pathway.…”

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confidence: 99%

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NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

et al. 2015

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NF-κB-inducing kinase (NIK) is well-known for its role in promoting p100/NF-κB2 processing into p52, a process defined as the alternative, or non-canonical, NF-κB pathway. Here we reveal an unexpected new role of NIK in TNFR1-mediated RIP1-dependent apoptosis, a consequence of TNFR1 activation observed in c-IAP1/2-depleted conditions. We show that NIK stabilization, obtained by activation of the non-death TNFRs Fn14 or LTβR, is required for TNFα-mediated apoptosis. These apoptotic stimuli trigger the depletion of c-IAP1/2, the phosphorylation of RIP1 and the RIP1 kinase-dependent assembly of the RIP1/FADD/caspase-8 complex.In the absence of NIK, the phosphorylation of RIP1 and the formation of RIP1/FADD/caspase-8 complex are compromised while c-IAP1/2 depletion is unaffected. In vitro kinase assays revealed that recombinant RIP1 is a bona fide substrate of NIK. In vivo, we demonstrated the requirement of NIK pro-death function, but not the processing of its substrate p100 into p52, in a mouse model of TNFR1/LTβR-induced thymus involution. In addition, we also highlight a role for NIK in hepatocyte apoptosis in a mouse model of virus-induced TNFR1/RIP1-dependent liver damage. We conclude that NIK not only contributes to lymphoid organogenesis, inflammation and cell survival but also to TNFR1/RIP1-dependent cell death independently of the alternative NF-κB pathway.

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Section: Resultsmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

et al. 2015

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“…35,36,44 This conclusion is supported by the following lines of evidence: First, the TNFacatching antibody Enbrel fails to prevent BV6-induced cell death in primary CLL cells. Similarly, we recently described that BV6/Dexamethasone-induced cell death in childhood ALL occurs in a TNFa-independent manner.…”

Section: Discussionmentioning

confidence: 79%

“…1B and 2), in line with the reported function of Smac mimetic to trigger NF-jB activation upon depletion of cIAP proteins. 16,35 As Smac mimetics have been described to engage an NFjB-mediated, TNFa-driven autocrine/paracrine cell death loop, 9,16,35,36 we next investigated whether TNFa is required for BV6-induced cell death in primary CLL cells. However, addition of the TNFa-blocking antibody Enbrel failed to protect primary CLL cells against BV6-induced cell death (Fig.…”

Section: Bv6 Triggers Ciap Degradation Nf-jb Activation and Tnfaindementioning

confidence: 99%

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

Opel

Schnaiter

Dodier

et al. 2015

Intl Journal of Cancer

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Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-jB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-jB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)a, as zVAD.fmk, necrostatin-1 or TNFa-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups.Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western world. 1 Key prognostic factors besides the Rai and Binet stage are chromosomal aberrations like 17p or 11q deletion, TP53 mutation and immunoglobulin heavy-chain variable region gene (IGVH) mutation status. Although individualized therapeutic strategies have been developed, the disease is still incurable. Especially patients with 17p deletion and TP53 mutation have a very poor prognosis. 2 Therefore, new therapeutic targets that act independently of functional p53 in CLL are needed.CLL is characterized by the accumulation of Blymphocytes which has been largely attributed to defective cell death pathways rather than to aberrant proliferation. [3][4][5] Apoptosis represents one of the key forms of programmed cell death. 6 Necroptosis is a caspase-independent mode of programmed cell death that typically occurs when essential factors of apoptosis such as caspases are inhibited and is regulated by RIP1 and RIP3. 7 Inhibitor of apoptosis (IAP) proteins are major regulators of cell death and survival processes. X-linked inhibitor of apoptosis (XIAP) acts as direct caspase inhibitor, 8 while cIAP1 and -2 were shown to protect cells from cell death by acting primarily as E3 ubiquitin liga...

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The non‐peptidomimetic IAP antagonist ASTX660 sensitizes colorectal cancer cells for extrinsic apoptosis

Knoll

Ehrenschwender

2021

FEBS Open Bio

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Apoptosis resistance worsens treatment response in cancer and is associated with poor prognosis. Inhibition of anti‐apoptotic proteins can restore cell death and improve treatment efficacy. cIAP1, cIAP2, and XIAP belong to the inhibitor of apoptosis protein (IAP) family and block apoptosis. Targeting IAPs with peptides or peptidomimetics mimicking the IAP‐antagonizing activity of the cell's endogenous IAP antagonist SMAC (SMAC mimetics) showed promising results and fueled development of novel compounds. ASTX660 belongs to the recently introduced class of non‐peptidomimetic IAP antagonists and successfully completed phase I clinical trials. However, ASTX660 has thus far only been evaluated in few cancer entities. Here, we demonstrate that ASTX660 has cell death‐promoting activity in colorectal cancer and provide a head‐to‐head comparison with birinapant, the clinically most advanced peptidomimetic IAP antagonist. ASTX660 facilitates activation of the extrinsic apoptosis pathway upon stimulation with the death ligands TNF and TRAIL and boosts effector caspase activation and subsequent apoptosis. Mechanistically, ASTX660 enhances amplification of death receptor‐generated apoptotic signals in a mitochondria‐dependent manner. Failure to activate the mitochondria‐associated (intrinsic) apoptosis pathway attenuated the apoptosis‐promoting effect of ASTX660. Further clinical studies are warranted to highlight the therapeutic potential of ASTX660 in colorectal cancer.

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IAP Antagonists Target cIAP1 to Induce TNFα-Dependent Apoptosis

Cited by 1,016 publications

References 35 publications

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

The non‐peptidomimetic IAP antagonist ASTX660 sensitizes colorectal cancer cells for extrinsic apoptosis

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